Under normal conditions, the heart prefers NEFA as its source of ATP production. It has long been recognized that the acutely injured or chronically failing myocardium has a preference for glucose as its metabolic source for oxidative phosphorylation and ATP production. Davila-Roman V G, Vedala G, Herrero P, et al., “Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy,” J. Amer. Coll. Cardiol., 2002 40:271–277; Paolisso G, Gambardella A, Galzerano D, et al., “Total-body myocardial substrate oxidation in congestive heart failure,” Metabolism, 1994; 43:174–179; Depre C, Rider M H, Hue L., “Mechanisms of control of heart glycolysis,” Eur. J Biochem., 1998;258:277–290, all of which are incorporated by reference herein. This preference is based upon the biochemistry of glucose oxidation in which the complete beta oxidation of mole of glucose is associated with less consumption of oxygen for the amount of ATP produced (3.17 moles ATP/O2 molecule consumed) compared to the complete oxidation of a mole of NEFA (2.83 moles ATP/O2 molecule consumed). Following myocardial injury, the reduced oxygen requirements favor the oxidation of glucose. Furthermore, this shift in metabolic preference is mediated by changes in the molecular expression of rate limiting steps in both NEFA and glucose oxidation [Razeghi P, Young M E, Alcorn J L, et al., “Metabolic gene expression in fetal and failing human heart,” Circulation, 2001; 104:2923–2931, incorporated by reference herein], attesting to its evolutionary advantage.
As heart failure progresses from a compensated to a decompensated state, there is a reduction in creatine phosphate and eventual depletion of high energy phosphate stores. Shen W, Asai K, Uechi M, et al., Ingwall J S, “Progressive loss of myocardial ATP due to a loss of total purines during the development of heart failure in dogs,” Circulation, 1999; 100: 2113–2118, incorporated by reference herein. The depletion of the heart's required source of energy leads to further contractile dysfunction and hemodynamic decompensation that characterizes the advanced stages of heart failure. It has been observed that the failing heart in its advanced stage becomes resistant to the action of insulin, and, therefore, demonstrates reduced glucose uptake and oxidation. This occurs at a time when the failing heart capacity for using alternate substrates (NEFA) has been modified at a transcriptional level. Razeghi P, Young M E, Alcorn J L, et al., “Metabolic gene expression in fetal and failing human heart,” Circulation, 2001; 104:2923–2931, incorporated by reference herein. Taken together, these factors lead to a state of further energy deprivation, ATP depletion, and progressive heart failure.
GLP-1 (7–36 amide) or GLP-1 (7–39) are peptides produced by the L cells in the ileum. Drucker D J, “Biological actions and therapeutic potential of the glucagons-like peptides,” Gastroenterology, 2002; 122:531–44, incorporated by reference herein. It is one of three peptides (GLP-1, GLP-2, and GIP) from the glucagon-secretion family, that have been indicated in the control of appetite and satiety. These pro-glucagon derived peptides are secreted in response to nutrient ingestion, and GLP-1 and GIP act as incretins to stimulate insulin secretion. Importantly, these two peptides are glucose dependent and the insulinotropic action is attenuated at plasma glucose levels of less than 4 mmol/L. Therefore, GLP-1 stimulated insulin release is carefully controlled in an autocrine fashion, minimizing the risks of hypoglycemia that are associated with exogenous insulin administration. In addition, GLP-1 and its analogues have insulin-independent actions, including the inhibition of gastric emptying, reduction of food ingestion, beta islet cell hypertrophy, and, importantly, the inhibition of glucagon. GLP-1 is rapidly degraded by dipeptidase IV to a 9–36 peptide that also stimulates glucose uptake in insulin independent fashion. Thus, the purpose of the present invention is preferably to take advantage of the unique properties of GLP-1 to facilitate myocardial glucose uptake and oxidation in heart failure—a newly recognized insulin resistant state in which the heart is critically dependent upon glucose metabolism.
The unique property of GLP-1 to stimulate both insulin release in the presence of hyperglycemia and to suppress glucagon release has a favorable synergistic effect on myocardial glucose metabolism. Glucose uptake by the normally working heart is critically dependent on insulin mediated translocation of the Glut-4 transporter from cytosolic to the membrane compartment. Full activation of the insulin signaling cascade is a prerequisite for this important translocation. Once glucose is taken up into the cell, it may be either oxidated to generate ATP or stored as glycogen to serve as a readily available source of glucose in times of stress. However, most glucose undergoes oxidative metabolism through glycolysis and then enters the tricarboxylic acid cycle (TCA), where it is oxidized to acetyl-COA. The reducing elements generated in the TCA cycle then enter the electron transport chain, where ATP is generated. Insulin receptor stimulation is a prerequisite for both the uptake of glucose by the heart, and for the complete oxidation of glucose through aerobic glycolysis, through the phosphorylation of rate limiting enzymes. Shulman G I, “Cellular mechanisms of insulin resistance,” J. Clin. Invest., 2000;106;171–175, incorporated by reference herein.
Glucagon is a potent counter regulatory hormone to the action of insulin. Glucagon is released by the alpha-islet cells of the pancreas and increases circulating glucose by simulating glycogenolysis and gluconeogenesis through conventional β2 adrenergic receptor-cyclic AMP dependent mechanisms. Glucagon is responsible for the recruitment of carnitine and for the activation of CPT-1, a key rate limiting step in the trans-mitochondrial transfer of acetyl-CoA that is critical in the oxidation of non-esterified fatty acids. Glucagon also stimulates NEFA oxidation by inhibiting acyl-CoA carboxylate and thereby reducing concentrations of malonyl CoA. Therefore, glucagon favors fatty acid uptake and oxidation by the heart-limiting glucose oxidation, whereas insulin favor glucose uptake and oxidation by the heart.
By taking advantage of its unique properties, GLP-1 (7–36 amide) or its rapidly cleaved metabolite, GLP-1 (9–36 amide) favorably influences both glucose uptake through its insulinotropic and insulinomimetic mechanisms, at the same time suppressing glucagon, and, therefore, free fatty acid oxidation. The same is true for GIP.
Glucagon-like peptide-1 (GLP-1) has been studied extensively in the treatment of Type II diabetes, largely considered to be an insulin resistant state, in which pancreatic insulin reserves are reduced. Mauvais-Jarvis F, Andreelli F, Hanaire-Broutin H, Charbonnel B, Girard J., “Therapeutic perspectives for type 2 diabetes mellitus: molecular and clinical insights,” Diabetes Metab., 2001 Sep.; 27 (4 Pt 1):415–23, incorporated by reference herein. The efficacy in ameliorating the diabetes management is well established. Furthermore, GLP-1 has been shown to be safe and effective in both young and elderly Type II diabetics. DeLeon M J, Chandurkar V, Albert S G, Mooradian A D. “Glucagon-like peptide-1 response to acarbose in elderly type 2 diabetic subjects”, Diabetes Res. Clin. Pract., 2002 May; 56 (2):101–6, incorporated by reference herein; Meneilly et al., “Effect of Glucagon-Like Peptide-1 on Non-Insulin Mediated Glucose Uptake in the Elderly Patient with Diabetes,” Diabetes Care, 2001; 24:1951–56, incorporated by reference herein; Maneilly et al., “Glucagon-Like Peptide-1 (7–37) Augments Insulin Mediated Glucose Uptake in Elderly Patients with Diabetes,” J. Serentol. Med. Sci., 2001:56A; M6815, incorporated by reference herein. GLP-1 is rapidly metabolized to the 9–36 amino acid, which is ultimately excreted by the kidney. Therefore, the action of GLP-1 is prolonged in the presence of renal insufficiency.
GLP-1, its derivatives, analogs and pharmaceutically-acceptable salts thereof has also been used during the treatment of patients with acute heart attacks. The present invention is directed for use in heart failure, which is a chronic consequence of not only heart attacks, but hypertension, valvular disease and other CV conditions. See U.S. Pat. No. 6,277,819, incorporated by reference herein, by Efendic. This patent deals with acute treatment during a heart attack while the present invention treats the patient chronically, who has LV dysfunction.